Structure–Activity Relationship Studies with Tetrahydroquinoline Analogs as EPAC Inhibitors

EPAC proteins are
therapeutic targets for the potential treatment
of cardiac hypertrophy and cancer metastasis. Several laboratories
use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1
in various disease states. Here, we report SAR studies with tetrahydroquinoline
analogs that explore various functional groups. The most potent EPAC
inhibitor 12a exists as a mixture of inseparable E (major) and Z (minor) rotamers. The rotation
about the N-formyl group indeed impacts the activity
against EPAC.